title: Substituted pyrazolo[3,4-b]pyridines as human A1 adenosine antagonists: developments in understanding the receptor stereoselectivity.
abstract: A(1) adenosine receptor antagonists have been proposed to possess an interesting range of potential therapeutic applications. We have already reported the synthesis and the biological characterization of a family of pyrazolo[3,4-b]pyridine derivatives as A(1) adenosine ligands endowed with an antagonistic profile. In the present work, we report the LC separation of enantiomers of our most active A(1) antagonists together with the determination of their absolute configuration by means of X-ray crystal structure analysis. Biological assays confirmed a different activity for the two enantiomers, with the R one showing the higher human A(1)AR affinity. We also developed a homology model of this receptor subtype in order to suggest a binding disposition of the ligands into the hA(1)AR. All of the obtained data suggest that the compound's chirality plays a key role in A(1) affinity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Alessandra Tania
authors.initials: AT
authors.lastname: Zizzari
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Francesca
authors.initials: F
authors.lastname: Musumeci
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014162:Transfection
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines; D043682:Receptor, Adenosine A1